Protein Misdirection Inside and Outside Motor Neurons in Amyotrophic Lateral Sclerosis (ALS): A Possible Clue for Therapeutic Strategies

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.     

Electronic specific heat of La2−xSrxCu1−yMyO4(M=Ga,Zn): Impurity effects on a D-wave superconductor

The electronic specific heat C_el was studied in Ga- and Zn-doped La_2–xSr_xCuO₄ (0.16x0.22) at T10K. Partial substitution of Ga or Zn for Cu suppresses T_c and revives the T-linear electronic specific heat, T, markedly. The (y)/n vs T_c/T_c0 relation for Zn-doped samples with x0.2 is in good agreement with the theoretical one for resonant impurity scattering in a d-wave superconductor, while those for Ga-doped samples and for Zn-doped samples with x 0.2 deviate slightly from the theoretical curve. The deviation will be discussed in relation to changes in the magnetic properties of 3d electrons.     

Modification of Odor Investigation and Discrimination in Female Opossums (Monodelphis domestica) Following the Ablation of the Accessory Olfactory Bulbs.

To determine whether the vomeronasal system of the Brazilian short-tailed opossum (Monodelphis domestica) is important to the response to conspecific chemical signals, the authors tested female opossums with conspecific odors, before and after ablation of their accessory olfactory bulbs (AOBs). Anesthesia and sham treatments did not modify females' discrimination of conspecific odors when tested against water, between male and female odors, or between different odors from the same male donors. Odor investigation was partially diminished following partial ablation of the AOB, and complete ablation of the AOBs further impaired the ability of females to discriminate between certain odors. These findings provide the first evidence for the importance of the vomeronasal system in the detection of chemosignals of known origin in opossums. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metabolic Remodeling with Hepatosteatosis Induced Vascular Oxidative Stress in Hepatic ERK2 Deficiency Mice with High Fat Diets

We previously demonstrated the marked hepatosteatosis and endothelial dysfunction in hepatocyte-specific ERK2 knockout mice (LE2KO) with a high-fat/high-sucrose diet (HFHSD), but detailed metabolic changes and the characteristics in insulin-sensitive organs were not tested. This study aimed to characterize metabolic remodeling with changes in insulin-sensitive organs, which could induce endothelial dysfunction in HFHSD-LE2KO. The serum glucose and fatty acid (FA) were modestly higher in HFHSD-LE2KO than HFHSD-Control. FA synthesis genes were up-regulated, which was associated with the decreased phosphorylation of AMPK and ACC, and with the up-regulation of SREBP-1 in the liver from HFHSD-LE2KO. In FA and amino acids fraction analysis, arachidonic acid/eicosapentaenoic acid ratio, L-ornithine/arginine ratio, asymmetric dimethylarginine and homocysteine levels were elevated in HFHSD-LE2KO. Insulin-induced phosphorylation of AKT was blunted in skeletal muscle. Serum leptin and IL-1β were elevated, and serum adiponectin was decreased with the enlargement of epididymal adipocytes. Finally, the enhanced superoxide levels in the aorta, which were blunted with CCCP, apocynin, and tempol, were observed in HFHSD-LE2KO. A pre-incubation of aortic rings with tempol improved endothelial dysfunction in HFHSD-LE2KO. HFHSD-LE2KO revealed an acceleration of FA synthesis in the liver leading to insulin resistance in skeletal muscle and the enlargement of visceral adipocytes. Global metabolic remodeling such as changes in arginine metabolism, ω3/ω6 ratio, and adipocytokines, could affect the vascular oxidative stress and endothelial dysfunction in HFHSD-LE2KO.     

Characterization of a Large-Scale Nondoped YBa2Cu3O7−x Superconductor Prepared by Plastic Forming Without High-Pressure Molding

A slurry containing YBa₂Cu₃O_{7− x} particles and a fine YBa₂Cu₃(OH) _x colloid solution was prepared, and a large-scale bulk YBa₂Cu₃O_{7− x} superconductor (about 50 mm × 35 mm × 2 mm) was produced by plastic forming without high-pressure molding. The samples molded from the slurry were dried and then fired at 1223 K in air. X-ray diffraction data indicated that the samples had the characteristic orthorhombic YBa₂Cu₃O_{7− x} structure. Measurements of electrical resistance were carried out between 300 and 50 K by the standard four-probe DC electrical measurement. The samples began superconducting at an onset temperature around 92 K, and the full-transition temperature (critical temperature) ( T _c) was 88.7±1.4 K. The critical current density ( J _c) measured at 77 K was about 440 A/cm², the value of J _c was improved by the heat treatment under an oxygen atmosphere, and J _c=1.6 × 10³ A/cm² was observed. Under the magnetic field (B=1 T), the sample held its superconductivity, and demonstrated that this method can be used to produce the magnetic shielding used in magnetic resonance imaging diagnosis.     

Comparing the strength of query types in property testing: The case of k-colorability

We study the power of four query models in the context of property testing in general graphs, where our main case study is the problem of testing k-colorability. Two query types, which have been studied extensively in the past, are pair queries and neighbor queries. The former corresponds to asking whether there is an edge between any particular pair of vertices, and the latter to asking for the i ^th neighbor of a particular vertex. We show that while for pair queries testing k-colorability requires a number of queries that is a monotone decreasing function in the average degree d, the query complexity in the case of neighbor queries remains roughly the same for every density and for large values of k. We also consider a combined model that allows both types of queries, and we propose a new, stronger, query model, related to the field of Group Testing. We give upper and lower bounds on the query complexity for one-sided error in all the models, where the bounds are nearly tight for three of the models. In some of the cases, our lower bounds extend to two-sided error algorithms. The problem of testing k-colorability was previously studied in the contexts of dense graphs and of sparse graphs, and in our proofs we unify approaches from those cases, and also provide some new tools and techniques that may be of independent interest.     

Full penetration welding of thick high tensile strength steel plate with high-power disk laser in low vacuum

This study was undertaken in order to investigate the effect of reduced ambient pressure from an atmospheric pressure (101 kPa) to 0.1 kPa on one-pass full penetration welding of thick high-tensile strength steel plate of 23 mm thickness. A 16 kW disk laser of 1030 nm in wavelength was employed to weld HT980 grade plates at the speed of 5–25 mm/s. In partial penetration welding, it was revealed that humping phenomena occurred easily. Full penetration welding of the high-tensile strength steel plates could not be achieved at 101 kPa. On the other hand, full penetration welding was obtained at the welding speed of less than 20 mm/s at the pressure of less than 10 kPa. Especially, at 0.1 kPa, and 17 and 20 mm/s, sound weld joints without defects were obtained. According to the observation results of a keyhole inlet and a surface molten pool during welding with a high-speed video camera, the melt in front of a keyhole was smaller and the behaviour of a keyhole and a plume was much more stable at 0.1 kPa than at 101 kPa. Moreover, in the full penetration welding, spattering was suppressed under the proper conditions. Such phenomena became more stable in fast welding. It was revealed in laser welding of thick high-tensile strength steel plates that the formation of narrow I-shaped weld beads by achieving full-penetration welding in low vacuum was essential for the production of sound welds without defect.     

Decomposition of adsorbed VX on activated carbons studied by 31P MAS NMR

The fate of the persistent OP nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) on granular activated carbons that are used for gas filtration was studied by means of 31P magic angle spinning (MAS) NMR spectroscopy. VX as vapor or liquid was adsorbed on carbon granules, and MAS NMR spectra were recorded periodically. The results show that at least 90% of the adsorbed VX decomposes within 20 days or less to the nontoxic ethyl methylphosphonic acid (EMPA) and bis(S-2-diisopropylaminoethane) {(DES)2}. Decomposition occurred irrespective of the phase from which VX was loaded, the presence of metal impregnation on the carbon surface, and the water content of the carbon. Theoretical and practical aspects of the degradation are discussed.     

4D printing shape memory polymers for dynamic jewellery and fashionwear

4D printing is a novel approach that enables dynamic functionality in ordinary static object. We used a methacrylated semicrystalline polymer to print objects exhibiting thermally triggered shape memory behaviour. By exploring various molecular weights, it was found that a methacrylated polycaprolactone polymer with a number average molecular weight of 10,000?g?mol^?1 exhibited the best thermal and mechanical behaviour. The effect of dyes’ addition to the ink formulation on the photopolymerisation and on the printing processes was evaluated. The ink was utilised for demonstrating fabrication of dynamic jewellery and a shoe accessory by Digital Light Processing printing.     

Pseudogap Behavior in the Electronic Specific Heat of La2−xSrxCuO4

In La214, the electronic specific heat coefficient (=C _el /T) is gradually suppressed with lowering T below a certain temperature T* (> T _c ), where the in-plane resistivity and magnetic susceptibility also tend to be suppressed slightly. Temperature T*, increasing with lowering x, is in qualitative agreement with the mean field T _c (T _co ), estimated from the superconducting gap amplitude 2 _o at T T _c , as the onset temperature T* of a pseudogap in Bi2212. The gradual suppression of below T _co implies that a pseudogap will also open up below T _co in La214 as in Bi2212. In underdoped samples, whose pseudogap-like behaviors in C _el(T) become marked, the anomaly of C _el around T _c is rather different from the BCS expectation.